Osteoporosis is characterized by a reduction in the mass of bone per unit volume. Hence, therapies directed towards improving the bone forming cells should provide amelioration for the patients. Most of the therapy for osteoporosis so far involves treatments with purified recombinant proteins or drugs that show only modest effects and also are short lived and expensive. Hence, development of novel therapeutic strategies are needed to improve the pathophysiology of the disease. Gene therapy approaches using the adeno-associated virus (AAV) vectors have the potential for the long-term treatment of osteoporosis. AAV is a non-pathogenic vector that stable integrates into host genome. AAV infects both dividing and non-dividing cells in vitro and in vivo. We hypothesize that autologous transplantation of bone marrow stromal cells, transduced ex vivo with recombinant AAV encoding bone morphogenetic protein (BMP) gene sequences should provide a constant source of osteoblast production in vivo. The hypothesis is based on the recent identification that the pluripotent bone marrow stromal cells (MSCs) differentiate into bone-forming osteoblasts and also that expression of the key proteins of TGF-beta family, particularly the BMPs, precisely regulate this process. The relatively easy methods to isolate and expand the MSCs offer an ideal source for autologous gene therapy. Our preliminary results also indicate that the recombinant AAV vectors transduce the ex vivo expanded human and murine MSCs in high efficiency. Hence, by using rAAV vectors to transduce the ex vivo expanded human and murine MSCs in high efficiency. Hence, by using rAAV vectors to transduce the MSCs we plan to achieve increased bone density. Further, we hypothesize that by using osteoprogenitor cell- specific promoters to regulate the expression of BMP genes using AAV vectors, we will also accomplish osteopoietic differentiation of the ex vivo modulated MSCs and regulate the expression of BMP-2 only in bone forming cells. Thus, in the present preclinical pilot studies, we propose to systematically evaluate the efficiency of rAAV vectors for the treatment of osteoporosis in an osteopenic rat model. A successful outcome of these studies should lead to the development of novel treatment modalities for osteoporosis in an osteopenic rat model. A successful outcome of these studies should lead to the development of novel treatment modalities for osteoporosis and other osteopenic bone diseases in future.